Chirality-Governed UCST Behavior in Polypeptides

Natural and synthetic polypeptides with upper critical solution temperature (UCST) behavior have attracted extensive interest due to their applications in the biomedical fields. However, the relationship between the chirality and the UCST behavior of polypeptides has heretofore been scarcely investigated. Herein, chiral and racemic polypeptides with different side chains were synthesized to study the influence of chirality of amino acid residues on the UCST behavior of polypeptides. The chiral polypeptide undergoes a reversible, sharp, and thermally triggered UCST phase transition, whereas the racemic one exhibits no phase transition upon heating or cooling. Circular dichroism and 1H NMR measurements unveil that the formation of intramolecular hydrogen bonds between homochiral amino acid residues stabilize the helical secondary structure and the helical structure protrude outward side chains from each repeat unit to increase the availability of the side chains for intermolecular hydrogen bonds, resulting in the aggregation of polypeptides as structural motifs. Notably, the UCST behaviors of polypeptides can be designed with Tcp from 33.7 to 50.1 °C by regulating the content of hydroxyl- and hexyl-terminated side chains. Furthermore, these chiral polypeptides exhibit excellent degradability by proteinase K, and this biodegradability is regulated by the ratio of hydrophobic side chains. Our study not only sheds light on the chirality-governed structure–property relationship in polypeptides but also offers guidance for the rational design of thermoresponsive synthetic polypeptides and proteins in the fields of materials science, biotechnology, and medicine.